Effects of acetaminophen on prenatal brain development: an organoid model

摘要 扑热息痛(N-乙酰-对氨基酚，APAP)，又称扑热息痛，广泛用于妊娠期 减轻疼痛和退烧。然而，越来越多的研究表明，APAP可能会带来负面影响 影响胎儿和出生后早期发育，包括多器官系统。关于 神经发育，大规模队列的流行病学研究报告了显著增加的风险 产前儿童注意缺陷多动障碍和自闭症谱系障碍 暴露于APAP。特别是妊娠中期和晚期胎儿的大脑发育 根据流行病学和动物模型研究，似乎特别容易感染APAP。尽管坚挺 对胎儿潜在不良后果的证据，APAP影响人类胎儿的机制 大脑仍未被开发。在这里，我们建议使用人类功能脑器官模型来解决 这个问题。脑有机化合物非常适合这个项目，因为它们概括了人类胎儿的大脑。 转录和网络活动水平的发展，正如我们和其他人所证明的那样。我们 APAP通过转录程序失调影响胎儿大脑发育的假说 参与早期神经发生和突触信号传递。我们将通过以下方式验证这一假设 具体目标：(1)确定细胞和分子途径、细胞群体和共表达模块 胎脑发育过程中APAP暴露的调节失调；(2)研究突触和长时程增强 APAP暴露反应的振荡网络活动表型，以评估其对脑功能的影响。 我们的研究将填补孕期APAP暴露安全性的知识空白，使用相关的 人源性脑器官模型。此外，它还将提供APAP通过哪些分子机制 扰乱胎儿大脑发育并导致神经发育疾病。

SUMMARY Acetaminophen (N-acetyl-p-aminophenol (APAP), also known as paracetamol) is widely used in pregnancy for pain and fever reduction. However, an increasing number of studies suggest that APAP could negatively influence fetal and early postnatal development, including multiple organs systems. Regarding neurodevelopment, epidemiological studies of large cohorts have reported a significantly increased risk of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children prenatally exposed to APAP. In particular, fetal brain development during the second and third trimesters of pregnancy appears especially vulnerable to APAP based on the epidemiological and animal model studies. Despite strong evidence for potential adverse consequences to the fetus, the mechanism by which APAP impacts human fetal brain remains unexplored. Here, we are proposing to use human functional brain organoid models to address this question. Brain organoids are a perfect fit for this project because they recapitulate human fetal brain development at the transcriptional and network activity levels, as demonstrated by us and others. We hypothesize that APAP impacts fetal brain development by dysregulating transcriptional programs involved in early neurogenesis and synaptic signaling. We will test this hypothesis through the following Specific Aims: (1) Identify cellular and molecular pathways, cell populations, and co-expression modules dysregulated by APAP exposure during fetal brain development; (2) Investigate synaptic and long-term oscillatory network activity phenotypes in response to APAP exposure to evaluate its impact on brain function. Our study will fill in the knowledge gap regarding the safety of APAP exposure in pregnancy using relevant human-derived brain organoid models. In addition, it will provide molecular mechanisms by which APAP could disrupt fetal brain development and lead to neurodevelopmental diseases.